ABSTRACT New prophylactic approaches are needed to prevent acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Despite prophylaxis with current strategies, 30-70% of recipients still develop acute GVHD. Development of GVHD is the leading cause of morbidity and non-relapse mortality after allogeneic HCT, and limits the health-related quality of life (HRQOL) of patients and their ability to return to activities of daily living. Over the last two decades, our multidisciplinary team has been investigating the use of histone deacetylase (HDAC) inhibition (vorinostat) to prevent GVHD. In adult patients, we have completed a first-in-human phase I/II trial in related donor, reduced intensity conditioning allogeneic HCT (NCT00810602), and a phase II trial in unrelated donor, myeloablative conditioning allogeneic HCT (NCT01790568), both indicating safety of vorinostat, possible attenuation of GVHD without compromising the beneficial graft versus leukemia (GVL) effect, and potential neuroprotective effects (NCT02409134). Pediatric patients undergoing allogeneic HCT may also benefit from vorinostat to prevent GVHD, but have faced barriers of access to this potentially life-saving therapy. We have already submitted an application and obtained an IND from the FDA to conduct a phase I/II trial of vorinostat in addition to standard GVHD prophylaxis for pediatric patients undergoing unrelated donor myeloablative conditioning HCT. The purpose of this grant is to fund the phase I/II clinical trial of vorinostat in pediatric HCT. The phase I portion of the study will enroll up to 12 subjects aged 3? 21 years and will determine the recommended phase II dose (RP2D) of vorinostat using a 3+3 up-or-down algorithm. The single-arm phase II portion of the study will enroll an additional 37 subjects to receive vorinostat at the RP2D and will determine the incidence of grade II-IV acute GVHD at day 100 post-HCT. The objective of this early phase trial in pediatric HCT is to assess dose, safety, pharmacokinetics, pharmacodynamics, and the RP2D of vorinostat. Important additional endpoints include correlative laboratory studies, cognitive function, and patient-reported outcomes of HRQOL. We hypothesize that HDAC inhibition with vorinostat regulates the inflammatory response of GVHD and will correlate with preserved cognition and HRQOL. This study will enroll pediatric HCT patients for the following reasons: 1) There is a major unmet need of well-designed GVHD clinical trials in pediatric HCT that integrate clinical outcomes, biological function, cognitive assessments, and HRQOL measures; 2) Our previous pre-clinical and clinical data of HDAC inhibition for GVHD prevention in adult HCT provide biological correlates with relevance for mechanism of action; 3) HDAC inhibition may have neuroprotective properties and preserve HRQOL after allogeneic HCT, a treatment known to negatively impact cognitive function, particularly in patients receiving unrelated donor grafts, and potentially most significant in younger aged patients. Thus, this proposal will provide critical information on the safety, tolerability and preliminary efficacy of vorinostat in pediatric HCT to inform the development of a future, full-scale trial.